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Bacterial Regulation of Peripheral Immunity: Mechanistic insights from lactobacilli and Staphylococcus aureus
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a constant cross-talk between our immune system and the colonizing microbiota. The gut resident bacteria produce a broad range of molecules with regulatory activities in both local and distal tissues. Staphylococcus (S.) aureus is a commensal bacterium with high pathogenic potential due to production of several potent virulence factors including staphylococcal enterotoxins (SEs). These SEs are known to induce overwhelming T cell responses, which can result in a serious condition known as toxic shock syndrome. In contrast, several species of bacteria from the genus Lactobacillus exhibit probiotic features and promote beneficial physiological and immunological effects in its host. The underlying mechanisms behind bacterial activation and regulation of peripheral lymphocytes remain elusive. In this thesis, we explored how secreted factors present in the cell free supernatants (CFS) of cultured S. aureus and lactobacilli mechanistically impact the activation of different types of T cells and NK cells. In paper I, we investigated the influence of S. aureus-CFS and SEA on regulatory T cells and found that despite de novo induction of FOXP3 expression, TREG cells also produced pro-inflammatory cytokines, which associated with CD161-expression. In paper II, we could show that S. aureus-CFS and SEA induce proliferation, cytotoxicity and cytokine production in conventional and unconventional T- and NK cells. Moreover, we also showed that the lactobacilli-CFS were able to dampen immune cell activation, which was partly linked to lactobacilli-derived lactate. In paper III, we continued to investigate the mechanism behind Lactobacillus-mediated dampening of induced lymphocyte responses and identified extracellular membrane vesicles to be one of the main components involved in Lactobacillus-mediated regulation of cytokine responses. Other observations made in paper II brought about several questions regarding the ability of SEs to activate unconventional T- and NK cells, which lacks certain receptors known to be required for SE-mediated activation of conventional T cells. In paper IV, we therefore investigated the mechanism behind SE-mediated activation of γδ T-, MAIT- and NK cells and found that SEs indirectly activated γδ T- and NK cells, which required the presence of conventional αβ T cells. In summary, this thesis presents novel insights into how soluble components from bacteria modulate immune cell responses and extends the general understanding of bacterial influence on peripheral immunity. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2019. , p. 66
Keywords [en]
Immune regulation, Cytokines, T cells, gamma-delta T cells, MAIT cells, NK cells, Lactobacillus, Staphylococcus aureus, staphylococcal enterotoxins
National Category
Biological Sciences Immunology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-175184ISBN: 978-91-7797-861-9 (print)ISBN: 978-91-7797-862-6 (electronic)OAI: oai:DiVA.org:su-175184DiVA, id: diva2:1361247
Public defence
2019-11-29, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 09:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: Manuscript.

Available from: 2019-11-06 Created: 2019-10-15 Last updated: 2019-10-31Bibliographically approved
List of papers
1. Staphylococcus aureus-derived factors induce IL-10, IFN-gamma and IL-17A-expressing FOXP3(+)CD161(+) T-helper cells in a partly monocyte-dependent manner
Open this publication in new window or tab >>Staphylococcus aureus-derived factors induce IL-10, IFN-gamma and IL-17A-expressing FOXP3(+)CD161(+) T-helper cells in a partly monocyte-dependent manner
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22083Article in journal (Refereed) Published
Abstract [en]

Staphylococcus aureus (S. aureus) is a human pathogen as well as a frequent colonizer of skin and mucosa. This bacterium potently activates conventional T-cells through superantigens and it is suggested to induce T-cell cytokine-production as well as to promote a regulatory phenotype in T-cells in order to avoid clearance. This study aimed to investigate how S. aureus impacts the production of regulatory and pro-inflammatory cytokines and the expression of CD161 and HELIOS by peripheral CD4(+)FOXP3(+) T-cells. Stimulation of PBMC with S. aureus 161:2-cell free supernatant (CFS) induced expression of IL-10, IFN-gamma and IL-17A in FOXP3(+) cells. Further, CD161 and HELIOS separated the FOXP3(+) cells into four distinct populations regarding cytokine-expression. Monocyte-depletion decreased S. aureus 161:2-induced activation of FOXP3(+) cells while pre-stimulation of purified monocytes with S. aureus 161:2-CFS and subsequent co-culture with autologous monocyte-depleted PBMC was sufficient to mediate activation of FOXP3(+) cells. Together, these data show that S. aureus potently induces FOXP3(+) cells and promotes a diverse phenotype with expression of regulatory and pro-inflammatory cytokines connected to increased CD161-expression. This could indicate potent regulation or a contribution of FOXP3(+) cells to inflammation and repression of immune-suppression upon encounter with S. aureus.

National Category
Biological Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-128534 (URN)10.1038/srep22083 (DOI)000370925800001 ()26917055 (PubMedID)
Available from: 2016-04-06 Created: 2016-03-30 Last updated: 2019-10-15Bibliographically approved
2. Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells
Open this publication in new window or tab >>Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells
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2016 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 273Article in journal (Refereed) Published
Abstract [en]

Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human mucosal-associated invariant T cells (MAIT cells), gamma delta T cells, NK cells, as well as of conventional CD4(+) and CD8(+) T cells in vitro. Further, we investigated if lactobacilli-derived factors could modulate their activation. PBMC were cultured with S. aureus 161: 2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-gamma and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation.

Keywords
cell-free supernatant, immune modulation, lactobacilli, NK cells, probiotic, T cells, Staphylococcus aureus, superantigens
National Category
Biological Sciences Immunology in the medical area
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-132953 (URN)10.3389/fimmu.2016.00273 (DOI)000379401800001 ()27462316 (PubMedID)
Available from: 2016-08-30 Created: 2016-08-26 Last updated: 2019-10-15Bibliographically approved
3. Extracellular membrane vesicles from lactobacilli dampen IFN-γ responses in a monocyte-dependent manner
Open this publication in new window or tab >>Extracellular membrane vesicles from lactobacilli dampen IFN-γ responses in a monocyte-dependent manner
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(English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Refereed) Submitted
National Category
Immunology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-175181 (URN)
Available from: 2019-10-15 Created: 2019-10-15 Last updated: 2019-10-15Bibliographically approved
4. Activation of γδ T cells and NK cells by staphylococcal enterotoxins requires conventional T cells
Open this publication in new window or tab >>Activation of γδ T cells and NK cells by staphylococcal enterotoxins requires conventional T cells
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-175182 (URN)
Available from: 2019-10-15 Created: 2019-10-15 Last updated: 2019-10-15Bibliographically approved

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